FIGURE 2.

Schematic representation of the bone remodeling cycle with emphasis on the manifold roles played by matrix metalloproteinases. (A) Osteocytes detect mechanical stress or respond to biochemical stimuli. (B) Lining cells of the endosteal bone surface retract and proteases (e.g., MMPs) remove bone underlying membrane. (C) Osteoclasts are attracted and fused to become activated. (D) The underlying bone is digested by active multinucleated osteoclasts. (E) Osteoblasts are recruited to the bone resorption cavity. (F) New osteoid is formed by osteoblasts, and then mineralized (Datta et al., 2008; Fernandez-Patron et al., 2016; Paiva and Granjeiro, 2017; Cook et al., 2018). Other pathologies related to inactive/underactive MMPs are excessive inflammation, cardiovascular disorders, and metabolic dysregulation. MMP underactivity could also result from undesired side effects of common medications with MMP inhibitory actions (e.g., statins) (Cook et al., 2018). MSCs, mesenchymal stem cells; GFs, growth factors; RUNX2, runt-related transcription factor 2; RANKL, receptor activator of NF-kappa B ligand.